α-hydrdroxylic acid derivatives, their production and use

ABSTRACT

The present invention relates to carboxylic acid derivatives of the formula                    
     where the radicals have the meanings stated in the description, to the preparation of these compounds and to their use as drugs.

The present invention relates to novel α-hydroxy acid derivatives, their preparation and use.

Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. “Endothelin” or “ET” hereinafter signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).

Increased or abormal [sic] release of endothelin causes a persistent contraction in peripheral, renal and cerebral blood vessels, which may lead to disorders. As reported in the literature, endothelin is involved in a number of disorders; these include hypertension, myocardial infarct, heart failure, kidney failure, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, atherosclerosis, stroke, benign prostate hypertrophy and asthma (Japan J. Hyperteusion [sic] 12, 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328 1732 (1993), Nephton [sic] 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardist. 27, A234 (1995), Cancer Research 56, 663 (1996)).

A compound having the formula A

is mentioned in the European patent application with the file number P 44 36 851.8 (page 32, compound I-28). However, this compound cannot be prepared by the preparation process mentioned in this patent application.

Compounds of the formula B where R³ can be, for example, phenyl, and R² and R⁴ can be hydrogen or C₁-C₄-alkyl, are described in the European patent with the number 0 347 811 B1 as substances with herbicidal activity.

The invention relates to the α-hydroxy carboxylic acid derivatives of the formula I

where R is formyl, a tetrazole [sic], nitrile [sic], a group COOH or a radical which can be hydrolyzed to COOH. R is, for example, a group

where R¹ has the following meanings:

a) hydrogen

b) a succinylimidoxy [sic] group

c) a 5-membered heteroaromatic system, such as pyrrolyl, pyrazolyl-[sic] imidazolyl and triazolyl, which is linked via a nitrogen atom and which may carry one or two halogen atoms or one or two C₁-C₄-akyl or one or two C₁-C₄-alkoxy groups;

d) R¹ furthermore a group

where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R⁹ is C₁-C₄-alkyl, C₃-C₇-cycloalkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or unsubstituted or substituted phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, mercapto, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino;

e) R¹ furthermore a radical OR¹⁰, where R¹⁰ is:

hydrogen, the cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium, and physiologically tolerated alkylammonium ion or the ammonium ion;

C₃-C₈-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,

C₁-C₈-alkyl, in particular C₁-C₄-alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;

CH₂-phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino,

a C₃-C₆-alkenyl or C₃-C₆-alkynyl group, it being possible for this group in turn to carry one to five halogen atoms;

R¹⁰ can furthermore be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino;

a 5-membered heteroaromatic system which is linked via a nitrogen atom and contains one to three nitrogen atoms, and which may carry one or two halogen atoms and/or one or two of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloroimidazol-1-yl;

f) R¹ furthermore a radical

where R¹¹ is:

C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, it being possible for these radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio and/or a phenyl radical;

phenyl which is unsubstituted or substituted, in particular as mentioned above;

g) R¹ a radical

where R¹² has the same meanings as R¹¹;

h) R¹ can furthermore be

where R¹³ and R¹⁴ can be identical or different and have the following meanings:

hydrogen, C₁-C₇-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-alkanyl [sic], C₃-C₇-alkynyl, benzyl, phenyl, unsubstituted or substituted, as described above

or R¹³ and R¹⁴ together form a C₄-C₇-alkylene chain which is closed to a ring, is unsubstituted or substituted by C₁-C₄-alkyl, for example, and may contain a hetero atom, eg. oxygen, nitrogen or sulfur, such as —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₂—O—(CH₂)₂—, —(CH₂)₂—S—(CH₂)₂—, —CH₂—NH—(CH₂)₂—, —(CH₂)₂—NH—(CH₂)₂—.

The other substituents have the following meanings:

W nitrogen or C—NO₂, furthermore W can be a CH group when one or more of the substituents R², R³, R¹⁵ and/or R¹⁶ are a nitro group, or when X and/or Y are nitrogen;

R² is hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, hydroxyl, mercapto, C₁-C₄-alkylthio, nitro, amino, C₁-C₄-alkylamino or C₁-C₄-dialkylamino, cyano, phenyl, optionally substituted once to three times by halogen, hydroxyl, amino, mono- or dialkyl (C₁-C₃)-amino, C₁-C₃-alkyl, C₁-C₃-alkoxy, mercapto or C₁-C₃-alkylthio, carboxyl, C₁-C₃-alkylcarboxyl;

or

a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which carries one to three substituents as described above;

R² can furthermore form, with the adjacent carbon atom and X, a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by a hetero atom such as nitrogen, sulfur or oxygen, and which can be substituted once to three times by the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, amino, C₁-C₃-alkylamino, C₁-C₃-dialkylamino;

X is nitrogen or CR¹⁵ where R¹⁵ is hydrogen, nitro, C₁-C₅-alkyl or C₂-C₅-alkenyl, optionally substituted once or twice by hydroxyl, carboxyl or phenyl, which in turn can be substituted by C₁-C₃-alkyl, hydroxyl or carboxyl; C₁-C₆-alkoxy, C₁-C₆-alkylthio, phenyl, hydroxyl, mercapto, nitro, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, cyano or carboxyl;

it is furthermore possible for CR¹⁵ to be linked to R² to give a 5- or 6-membered ring as described above, or CR¹⁵ can form with R³ and its adjacent carbon atom a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur, and the 5- or 6-membered ring may optionally be substituted once to three times by the following radicals:

halogen, nitro, cyano, hydroxyl, mercapto, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, amino, C₁-C₃-alkylamino, C₁-C₃-dialkylamino or carboxyl; nitrogen in the 5-membered ring may also be substituted by a formyl or acetyl group;

R³ can have the same meanings as R², R² and R³ can be identical or different; it is furthermore possible for R³ to form with the adjacent carbon atom and with X a 5- or 6-membered ring as described above; it is furthermore possible for R³ to form together with the adjacent carbon atom and Y a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur; the 5- or 6-membered ring may optionally be substituted once to three times by the following radicals:

halogen, nitro, cyano, hydroxyl, mercapto, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, amino, C₁-C₃-alkylamino, C₁-C₃-dialkylamino or carboxyl; nitrogen in the 5-membered ring may also be substituted by a formyl or acetyl group;

Y is nitrogen or CR¹⁶ where R¹⁶ is hydrogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, nitro, phenyl, hydroxyl, halogen, cyano, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, mercapto or carboxyl, or CR¹⁶ forms together with R³ and its adjacent carbon atom a 5- or 6-membered ring as described above;

R⁴ is phenyl, naphthyl, dihydro- or tetrahydronaphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, phenyl, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino or C₁-C₄-dialkylamino, it being possible for two radicals on adjacent carbon atoms to form, together with the latter, a five- or six-membered ring which is linked by an alkylene or alkylidene [sic] group and in which one or more methylene or methylidene [sic] groups can be replaced by oxygen, such as —(CH₂)₃—, —(CH₂)₄—, —CH═CH—O—, —O—CH₂—O—, —O—(CH₂)₂—O—, —CH═CH—CH₂— or —O—CH═CH—O—;

R⁴ can be, for example, the following radicals:

R⁴ can furthermore be a five- or six-membered heteroaromatic system which contains a nitrogen, sulfur or oxygen atom and which can carry one or two of the following radicals: halogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenoxy, C₁-C₄-alkylthio, C₁-C₄-alkylamino or C₁-C₄-dialkylamino;

in addition, R⁴ and R⁵ can be phenyl groups which are connected together in the ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO₂—, NH— or N-alkyl group;

R⁵ can have the same meanings as R⁴, it being possible for R⁴ and R⁵ to be identical or different;

R⁶ is hydrogen, C₁-C₈-alkyl, C₂-C₈-alkenyl or C₃-C₈-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, nitro, cyano, C₁-C₄-alkoxy, hydroxyl, C₁-C₄-alkylthio, mercapto, C₁-C₄-haloalkoxy, carboxyl, C₁-C₄-alkylcarboxyl, C₁-C₄-alkylcarbonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino or phenyl, or naphthyl which can in turn be substituted one or more times by: halogen, nitro, cyano, hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, mercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino or phenoxy, R⁶ is furthermore C₁-C₄-alkyl which is substituted by phenoxymethyl in which the phenyl group can be substituted once or twice by halogen, methyl or methoxy;

R⁶ is furthermore also a C₁-C₈-alkyl, C₃-C₈-alkenyl or C₃-C₈-alkynyl chain which is substituted by of the following radicals:

a five- or six-membered heteroaromatic system which contains one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio;

or one of the following radicals:

The compounds and the intermediates II for preparing them may have one or more asymmetrically substituted carbon atoms. Such compounds may be in the form of pure enantiomers or pure diastereomers or of a mixture thereof. It is preferred to use an enantiomerically pure compound as active substance.

The invention furthermore relates to the use of the abovementioned amino acid derivatives for producing drugs, in particular for producing inhibitors for endothelin receptors.

The compounds according to the invention are prepared by reacting a hydroxy acid derivative II in which the substituents have the stated meaning with compounds of the general formula III,

where R¹⁷ is halogen or R¹⁸ —SO₂—, where R¹⁸ can be C₁-C₄-alkyl, C₁-C₄-haloalkyl or phenyl.

The reaction preferably takes place in an inert diluent with the addition of a suitable base, ie. a base which deprotinates the intermediate II, at a temperature in the range from room temperature to the boiling point of the solvent.

Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which may be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachoride, ethylene chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as ethyl acetate and amyl acetate, amides such as dimethylformamide and dimethylacetamide, sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane, and bases such as pyridine, N-methylpyrrolidone, cyclic ureas such as 1,3-dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. The reaction is preferably carried out at a temperature in the range from 0° C. to the boiling point of the solvent or mixture of solvents.

It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide, or tertiary amines, eg. triethylamine, pyridine, 4-N,N-dimethylaminopyridine, imidazole or diazobicycloundecane [sic].

The invention also relates to compounds of the formula II which are unknown. They can be prepared in a known manner.

For example, compounds of the formula II can be prepared by converting a nitrile of the formula IV, by alkylation with the aid of a base and of a compound R⁶—K, into a nitrile V

as described, for example, in Ca. J. of Chem. 47 (1969) 1587 et seq., where K is a leaving group such as halogen, tosylate, mesylate or triflate.

The nitrites V are then reduced to aldehydes VI as described in Synth. Comm. 19 (1989) 355 et seq. or J. Am. Chem. Soc. 107 (1985) 4577 et seq. Reducing agents which can be used are metal hydrides such as LiAlH₄ or (n-Bu)₂A1H.

The aldehydes VI are converted by known methods (as described, for example, in Chem. Pharm. Bull. 37 (1989) 2570-2) into the corresponding cyanohydrins VII:

Cyanohydrins VII can be converted by hydrolysis, for example with aqueous HCl, or by the Pinner method with HCl gas in alcohol R¹⁰OH, into α-hydroxy carboxylic acid derivatives II where

Compounds II can also be prepared by diazotizing an amino acid derivative VIII by known methods, eg. with sodium nitrite and aqueous sulfuric acid, and hydrolyzing to the hydroxy acid derivative II as described, for example, in Synthesis (1987), 479-80.

Amino acid derivatives VIII can be prepared, for example, in a Strecker reaction from the aldehydes VI, eg. as disclosed in Angew. Chem. Int. Ed. 26 (1987), 557 et seq.

In addition, compounds VIII can be prepared by reacting a compound IX with a Grignard compound X, and hydrolyzing the product XI with acid to VIII, similar to the description in Liebigs Ann. (1977) 1174-1182:

Compounds II can furthermore be synthesized by electrophilic oxidation of carboxylic acid derivatives XII, eg. with oxygen after deprotonation, as described in Tetrahedron Letters 21 (1975) 1731-4, or with Davis' reagent

as described in J. Org. Chem. 47 (1982) 1775-77.

Compounds XII can be prepared by reacting a suitable phosphonate compound XIII with a carbonyl compound XIV in a Wittig-Horner reaction to give the unsaturated compound XV.

Compound XV can then be converted by a method from Chem. Ber. 64 (1931) 1493 et seq. with R⁵—H in the presence of a Friedel-Crafts catalyst such as aluminum trichloride into the carboxylic acid derivative XVI.

Compounds I can also be prepared by reacting cyanohydrins VII with compounds III to give nitrites XVII.

The reaction preferably takes place in an inert solvent with the addition of a suitable base as described previously.

Compounds XVII can then be converted in a known manner, for example by reaction with acids such as hydrochloric acid or sulfuric acid, with or without addition of an alcohol into compounds of type I.

Compounds of the formula I can be obtained in enantiomerically pure form by starting from enantiomeric compounds II, which can be prepared by classical racemate resolution or by enantioselective syntheses (such as, for example, Pure Appl. Chem., 55 (1983) 1799 et seq.; Helv. Chim. Acta, 71 (1988) 224 et seq.; J. Am. Chem. Soc, 110 (1988) 1547-1557; Chem. Eng. News (1989) 25-27) in enantiomerically pure and, where appropriate, diastereomerically pure form, and reacting these compounds II with III as described above. Another possibility for obtaining enantiomerically pure compounds of the formula I is classical racemate resolution of racemic or diastereomeric compounds I with suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, chinchonidine [sic], chinchonine [sic], yohimbine, morphine, dehydroabietylamine, ephedrine (−), (+), deoxyephedrine (+), (−), threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (−), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (−) threo-2-amino-1-phenyl-1,3-propanediol (+), (−), α-methylbenzylamine (+), (−), α-(1-naphthyl)ethylamine (+), (−), α-(2-naphthyl)ethylamine (+), (−), aminomethylpinone, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives and peptide derivatives.

Preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those where the substituents have the following meanings:

R a carboxylic acid, a carboxylic acid salt or a group which can be hydrolyzed to a carboxylic acid, as described above.

W nitrogen or C—NO₂;

X nitrogen or CR¹⁵ where R¹⁵ is hydrogen, nitro, C₁-C₅-alkyl or C₁-C₅-alkenyl, optionally substituted by hydroxyl, carboxyl or phenyl, which can in turn be substituted by C₁-C₃-alkyl, hydroxyl or carboxyl; C₁-C₄-alkoxy, C₁-C₄-alkylthio, hydroxyl, nitro, amino, cyano or carboxyl, or CR¹⁵ forms with R² and the adjacent carbon atom a 5- or 6-membered alkylene or alkylidene [sic] ring in which one or two carbon atoms can be replaced by a hetero atom such as nitrogen, oxygen or sulfur, and which can be substituted once or twice by a C₁-C₃-alkyl or C₁-C₃-alkoxy group; nitrogen in the 5-membered ring may additionally be substituted by a CHO or COCH₃ group;

R² hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, nitro, amino, methylamino, dimethylamino or cyano; R² can furthermore form with the adjacent carbon atom and X a 5- or 6-membered ring as described above;

R³ hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl, C₁-C₄-alkylthio, nitro, amino, methylamino, dimethylamino or cyano; R³ can furthermore form with the adjacent carbon atom and Y a 5- or 6-membered alkylene or alkylidene [sic] ring in which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur and which can be substituted once or twice by a C₁-C₃-alkyl or C₁-C₃-alkoxy group; nitrogen in the 5-membered ring may also be substituted by a formyl or acetyl group;

Y nitrogen or CR¹⁶ where R¹⁶ is hydrogen, C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, nitro, halogen, cyano, amino, methylamino, dimethylamino or carboxyl, or if CR¹⁶ forms together with R³ and its adjacent carbon atom a 5- or 6-membered ring as described above;

R⁴ is phenyl or naphthyl which can be substituted by one or more of the following radicals:

halogen, hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio or phenyl, and the aromatic system may furthermore be substituted, exclusively or in addition to the abovementioned radicals, by two radicals on adjacent carbon atoms which together represent a 1,3-dioxomethylene [sic] or 1,4-dioxoethylene [sic] group and form with the adjacent carbon atoms a 5- or 6-membered ring respectively;

in addition, R⁴ and R⁵ can be phenyl groups which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, or an oxygen or sulfur atom;

R⁵ can have the same meanings as R⁴, it being possible for R⁴ and R⁵ to be identical or different;

R⁶ is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl or C₃-C₆-alkynyl, it being possible for each of these radicals to be substituted once to three times by:

halogen, cyano, C₁-C₃-alkoxy, hydroxyl, C₁-C₃-alkylthio, mercapto, C₁-C₃-haloalkoxy, carboxyl, C₁-C₃-alkylcarboxyl or phenyl, or naphthyl which can likewise be substituted once to three times by the following radicals:

halogen, cyano, hydroxyl, C₁-C₃-alkoxy, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₃-haloalkoxy, mercapto, C₁-C₃-alkylthio, phenyl or phenoxy, or, exclusively or in addition to the abovementioned radicals, two radicals on adjacent carbon atoms may together represent a 1,3-dioxomethylene [sic] or 1,4-dioxoethylene [sic] group, and R⁶ can furthermore be a phenylmethoxymethyl, -ethyl or -propyl group in which the phenyl group is substituted by methyl, methoxy or halogen.

Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as mixture thereof, are those in which the substituents have the following meanings:

R a carboxylic acid, a carboxylic acid salt or a group which can be hydrolyzed to a carboxylic acid, as described above;

W nitrogen;

X nitrogen or CR¹⁵ where R¹⁵ is hydrogen, C₁-C₅-alkyl or C₁-C₅-alkenyl, optionally substituted by hydroxyl, carboxyl or phenyl, which can in turn be substituted by C₁-C₃-alkyl, hydroxyl or carboxyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, hydroxyl, cyano or carboxyl, or CR¹⁵ forms with R³ and the adjacent carbon atom a 5- or 6-membered alkylene or alkylidene [sic] ring in which one carbon atom can be replaced by oxygen and which can be substituted by a methoxy or methyl group;

for example, the 5- or 6-membered alkylene and alkylidene [sic] ring may have the following structures:

R² hydrogen, chlorine, methyl, ethyl, trifluoromethyl, nitro, methoxy, ethoxy, methylmercapto, amino, dimethylamino, methylamino; R² may furthermore form with the adjacent carbon atom and X a 5- or 6-membered ring as described above;

R³ hydrogen, chlorine, methyl, ethyl, trifluoromethyl, nitro, methoxy, ethoxy, methylmercapto, amino, methylamino or dimethylamino;

R³ may furthermore form with Y a 5- or 6-membered alkylene or alkylidene [sic] ring in which one or two carbon atoms may be replaced by nitrogen or oxygen, and which can be substituted by a methyl or methoxy group; examples of such alkylene or alkylidene [sic] rings are:

Y nitrogen or CR¹⁶ where R¹⁶ is hydrogen, nitro, methyl, ethyl, chlorine or cyano, or CR¹⁶ forms with R³ and its adjacent carbon atom a 5- or 6-membered ring as described above;

R⁴ is phenyl which carries one or two of the following radicals: halogen, hydroxyl, methoxy, ethoxy, C₁-C₃-alkyl, trifluoromethyl, methylmercapto, ethylmercapto or phenyl; it is furthermore possible for two substituents to represent a dioxomethylene [sic] group, exclusively or in addition to other substituents; examples of such groups representing R⁴ are:

in addition, R⁴ and R⁵ can be phenyl group [sic] which are connected together in ortho positions by a direct linkage, a methylene or ethylene group;

R⁵ can have the same meanings as R⁴, and R⁴ and R⁵ can be identical or different;

R⁶ is hydrogen, C₁-C₆-alkyl or C₃-C₆-alkenyl, it being possible for each of these radicals to be substituted once or twice by:

chlorine, cyano, hydroxyl, carboxyl, methoxy, ethoxy, methylmercapto, methylcarboxyl, phenylmethoxy, p-methylphenylmethoxy, p-methoxyphenylmethoxy, p-fluorophenylmethoxy, or phenyl which can be substituted once or twice by the following radicals:

chlorine, fluorine, cyano, hydroxyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methylmercapto, phenyl or phenoxy, or, exclusively or in addition to the abovementioned radicals, two radicals on adjacent carbon atoms may represent a 1,3-dioxomethylene [sic] group.

The compounds of the present invention offer a novel potential therapy for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, kidney failure caused by ischemia and by intoxication, and hypertension, and of cancers, in particular prostate cancer and skin cancer.

The good effect of the compounds can be shown in the following experiments:

Receptor Binding Studies

For binding studies, cloned human ET_(A) receptor-expressing CHO cells and guinea-pig cerebellar membranes with >60% ET_(B) relative to ET_(A) receptors were employed.

Membrane Preparation

The ET_(A) receptor-expressing CHO cells were grown in F₁₂ medium with 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. After neutralization with F₁₂ medium, the cells were collected by centrifugation at 300×g. For cell lysis, the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 10⁷ cells/ml of lysis buffer at 4° C. for 30 min. The membranes were centrifuged at 20,000×g for 10 min, and the pellet was stored in liquid nitrogen.

Guinea-pig cerebella were homogenized in a Potter-Elvejhem homogenizer and obtained by differential centrifugation at 1000×g for 10 min and repeated centrifugation of the supernatant at 20,000×g for 10 min.

Binding Assays

For the ET_(A) and ET_(B) receptor binding assays, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl₂, 40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of protein per assay mixture and incubated at 25° C. with 25 pM [125I [sic]]-ET₁ (ET_(A) receptor assay) or 25 pM [125I [sic]]-RZ₃ (ET_(B) receptor assay) in the presence and absence of test substance. The nonspecific binding was determined with 10⁻⁷ M ET₁. Filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) after 30 min separated the free and the bound radioligand, and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Functional in vitro assay system to search for endothelin receptor (subtype A) antagonists

This assay system is a functional, cell-based assay for endothelin receptors. Certain cell s show, when they are stimulated with endothelin 1 (ET1), an increase in the intracellular calcium concentration. This increase can be measured in intact cells which have been loaded with calcium-sensitive dyes.

1-Fibroblasts isolated from rats in which an endogenous endothelin receptor of the A subtype has been detected were loaded with the fluorescent dye Fura 2-an as follows: after trypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mm KCl, 1.5 mM MgCl₂, 1 mM CaCl₂, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2×10⁶/ml and incubated at 37° C. in the dark with Fura 2-am (2 μM), Pluronics [sic] F-127 (0.04%) and DMSO (0.2%) for 30 min. The cells were then washed twice with buffer A and resuspended at 2×10⁶/ml.

The fluorescent signal with Ex/Em 380/510 from 2×10⁵ cells per ml was continuously recorded at 30° C. The test substances and, after incubation for 3 min, ET1 were [lacuna] to the cells, the maximum change in fluorescence was determined. The response of the cells to ET1 without previous addition of a test substance served as control and was set equal to 100%.

In Vivo Testing of ET Antagonists

Male SD rats weighing 250-300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized [sic].

In control animals, intravenous administration of 1 μg/kg ET1 leads to a distinct rise in blood pressure which persists for a lengthy period.

The test compounds were injected i.v. (1 ml/kg) into the test animals 5 min before administration of ET1. To determine the ET-antagonistic properties, the rise in blood pressure in the test animals was compared with that in the control animals.

“Sudden Death” Induced by Endothelin-1 in Mice

The principle of the test comprises prevention of the sudden heart death caused in mice by endothelin, probably owing to constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg endothelin in a volume of 5 ml/kg of body weight is followed within a few minutes by the death of the animals.

The lethal endothelin-1 dose is checked on each occasion on a small group of animals. If the test substance is administered intravenously, usually the endothelin-1 injection which was lethal in the reference group takes place 5 min thereafter. With other modes of administration, the times between administrations are longer, where appropriate up to several hours.

The survival rate is recorded and doses which effectively protect 50% of the animals from endothelin-induced heart death for 24 h or longer (ED 50) are determined.

Functional Test on Vessels for Endothelin Receptor Antagonists

Firstly a contraction is induced with K⁺ in segments of rabbit aorta after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37° C. and a pH of 7.3-7.4. After washing out, an endothelin dose-effect plot is constructed up to the maximum.

Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before the start of the endothelin dose-effect plot. The effects of endothelin are calculated as a % of the K⁺ contraction. With effective endothelin antagonists, the endothelin dose-effect plot is shifted to the right.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally [sic]) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is from about 0.5 to 50 mg/kg of body weight on oral administration and from about 0.1 to 10 mg/kg of body weight on parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. For this purpose, the active substances can be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The forms obtained in this way normally contain from 0.1 to 90% by weight of active substance.

The invention further relates to the combination of compounds of the formula I with inhibitors of the renin-angiotensin system (RAS). RAS inhibitors are disclosed in, for example, EP 634 175.

The combinations according to the invention are suitable for treating disorders for which compounds of the formula I also show efficacy on their own, especially for treating hypertension and chronic heart failure.

The invention further relates to the use of a structural fragment of the formula (A)

where R—R⁶ have the meanings stated above for compounds of the formula I, as structural element in a pharmaceutically active compound with endothelin receptor-antagonizing action.

SYNTHESIS EXAMPLES Example 1 2,2-Diphenylpropional [sic]

50.0 g (0.241 mol) of 2,2-diphenylpropionitrile were dissolved in 200 ml of absolute diethyl ether, and 74.2 ml of a one-molar solution of LiAlH₄ in ether were added dropwise. The mixture was then refluxed for one hour and stirred at room temperature for 16 hours.

Then 29 ml of water were added, the organic phase was separated off, and the aqueous phase was extracted with ether. The combined organic phases were dried with MgSO₄, and the solvent was stripped off under reduced pressure. 52.1 g of oily crude product were obtained and were immediately reacted further.

Example 2 2-Hydroxy-3,3-diphenylbutyronitrile

42.3 g (0.201 mol of 2,2-diphenylpropionitrile [sic] were dissolved in 230 ml of THF, and 41.4 g (0.217 mol) of p-toluenesulfonic acid were added. Then 14.09 g (0.217 mol) of KCN in 60 ml of water were added dropwise. The mixture was then heated at 40° C. for 3 hours. The reaction mixture was concentrated to about 30% under reduced pressure, taken up in water and extracted three times with ethyl acetate. The combined organic phases were washed twice with sodium disulfite solution, dried with MgSO₄ and concentrated under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/ethyl acetate (20:1). 41.2 g (86%) of 2-hydroxy-3,3-diphenylbutyronitrile were obtained.

¹H-NMR [CDCl₃], δ=1.9 (s, 3H); 2,7 (d, 1H); 5.1 (d, 1H); 7.2-7.4 (m, 10H).

Example 3 Ethyl 2-Hydroxy-3,3-diphenylbutyrate

1.0 g (4.2 mmol) of 2-hydroxy-3,3-diphenylbutyronitrile was dissolved in 10 ml of ethanol, and 10 ml of conc. HCl [sic] were added. The mixture was refluxed for 24 hours, and then the solvent was stripped off under reduced pressure, and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic phases were washed with 10% strength NaOH, dried with MgSO₄ and concentrated under reduced pressure. 0.8 g (67%) of product was obtained.

¹H-NMR [CDCl₃], δ=0.9 (t, 3H); 1.8 (d, 3H); 3.0 (d, 1H); 3.9 (g, 2H); 5.0 (d, 1H); 7.1-7.4 (m, 10H).

Example 4 2-Hydroxy-3,3-diphenylbutyramide

10.0 g (4.22 [sic] mmol) of 2-hydroxy-3,3-diphenylbutyronitrile were dissolved in 500 ml of methanol (abs.) and, at 5-10° C., HCl was passed in for 3 hours. The mixture was then stirred at 5° C. for 3 hours and at room temperature for 16 hours. Then 200 ml of 6 molar HCl were added and the mixture was evaporated to dryness under reduced pressure. The crude product was recrystallized from an ethyl acetate/heptane mixture. 2.5 g (23%) of 2-hydroxy-3,3-dihenylbutyramide were obtained as a white solid.

Example 5 Ethyl 2-Hydroxy-3,3-diphenylbutyrate

2.15 g (8.4 mmol) of 2-hydroxy-3,3-diphenylbutyramide were dissolved in 15 ml of ethanol, 15 ml of conc. HCI were added and the mixture was refluxed for 40 hours. The solvent was stripped off under reduced pressure, and the residue was taken up in water. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed twice with 10% strength sodium hydroxide solution. Drying with MgSO₄ and stripping off the solvent under reduced pressure resulted in 1.75 g (73%) of ethyl 2-hydroxy-3,3-diphenylbutyrate.

Example 6 2-Hydroxy-3,3-diphenylbutyric Acid

1.75 g (6.2 mmol) of ethyl 2-hydroxy-3,3-diphenylbutyrate were dissolved in 10 ml of THF, and a solution of 0.23 g (9.3 mmol) of LiOH in 6 ml of water was added. The mixture was stirred at room temperature for 16 hours and at 40° C. for 4 hours. The mixture was subsequently concentrated under reduced pressure, taken up in water and washed with ethyl acetate. This was followed by acidification with HCl and extraction three times with ethyl acetate. The combined ethyl acetate phases were dried with MgSO₄, and the solvent was stripped off under reduced pressure. The residue was chromatographed on silica gel with CH₂Cl₂/MeOH (2:1). 0.80 g (50%) of 2-hydroxy-3,3-diphenylbutyric acid was obtained.

¹H-NMR [DMSO-d₆], δ=1.75 (s, 3H); 4.85 (s, 1H); 5.5 (s, broad, 1H)); 7.1-7.4 (m, 10H), 12.2 (s, broad, 1H).

Example 7 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3,3-diphenylbutyric Acid

0.29 g (9.5 mmol) of NaH were introduced into DMF and, under nitrogen, 0.80 g (3.15 mmol) of 2-hydroxy-3,3-diphenylbutyric acid in 3 ml of DMF were added. After stirring at room temperature for 30 minutes, 0.45 g (3.15 mmol) of 4,6-dimethyl-1,2-chloropyrimidine in 4 ml of DMF were added, and the mixture was stirred at RT for 16 hours. After the solvent had been stripped off under reduced pressure, the residue was taken up in water, acidified with HCl and extracted twice with ethyl acetate. The combined organic phases were dried with MgSO₄, and the solvent was stripped off under reduced pressure. The residue was chromatographed on silica gel with CH₂Cl₂/methanol (10:1).

0.37 g (32%) of 2-(4,6-dimethyl-2-pyridinyloxy)-3,3-diphenylbutyric [sic] acid of melting point 225-230° C. was obtained.

¹H-NMR [DMSO-d₆], δ=1.95 (s, 3H); 2.3 (s, 6H); 5.95 (s, 1H)); 6.8 (s, 1H); 7.0-7.45 (m, 10H).

The compound was fractionated into its two enantiomers by racemate resolution (see Table 2).

Example 8 Methyl 2-Hydroxy-3,3-diphenylbutyrate

15.0 g (63.3 mmol) of 2-hydroxy-3,3-diphenylbutyronitrile were dissolved in 250 ml of absolute methanol and, at 30-50° C., HCl was passed in to saturation. The mixture was then refluxed for 72 hours and subsequently concentrated under reduced pressure, and the residue was taken up in water. The aqueous phase was extracted three times with ethyl acetate; the combined organic phases were dried over MgSO₄, the solvent was stripped off under reduced pressure, and the residue was chromatographed on silica gel with n-heptane/ethyl acetate (20:1).

1.2 g (7%) of methyl 2-hydroxy-3,3-diphenylbutyrate were obtained.

¹H-NMR [CDCl₃], δ=1.8 (s, 3H); 2.95 (d, 1H); 3.45 (s, 3H)); 5.0 (d, 1H); 7.1-7.4 (m, 10H).

Example 9 Methyl 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyrate

1.2 g (4.4 mmol) of methyl 2-hydroxy-3,3-diphenylbutyrate were dissolved in 10 ml of absolute DMF and, under nitrogen, 1.2 g (8.8 mmol) of K₂CO₃ and 0.97 g (4.4 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for 16 hours. It was then evaporated, and the residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO₄ and concentrated. 1.8 g of crude product were obtained and were reacted further without purification.

¹H-NMR [CDCl₃], δ=2.0 (s, 3H); 3.25 (s, 3H); 3.9 (s, 6H)); 5.75 (d, 1H); 5.8 (s, 1H); 7.1-7.3 (m, 10H).

Example 10 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyric Acid

1.8 g (4.4 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyrate were dissolved in 25 ml of dioxane, and 26.5 ml (26.5 mmol) of a 1M KOH solution were added, and the mixture was stirred at 90° C. for 6 hours. The mixture was then concentrated, taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO₄ and evaporated. The residue was recrystallized from ethanol. 1.12 g (65%) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyric acid of melting point 229-234° C. were obtained.

¹H-NMR [DMSO-d₆], δ=1.9 (s, 3H); 3.85 (s, 6H); 5.85 (s, 1H)); 5.95 (s, 1H); 7.1-7.4 (m, 10H); 12.5 (s, broad, 1H).

Example 11 2,2-Diphenylbutyronitrile

173 ml (0.259 mol) of a 1.5 M solution of LDA in THF were added dropwise to a solution of 50.0 g (0.259 mol) of diphenylacetonitrile in 500 ml of THF (abs.) at −78° C. under argon, and the mixture was then stirred at −30° C. for one hour. Then, at −78° C., 28.23 g (0.259 mol) of ethyl bromide were added. The mixture was allowed to reach room temperature and was stirred for 16 hours. Subsequently, 80 ml of phosphate buffer (pH 7) were added and the mixture was evaporated. The residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO₄, and the solvent was stripped off under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/acetic acid (20:1). 38.2 g (67%) of 2,2-diphenylbutyronitrile were obtained.

Example 12 2,2-Diphenylbutyraldehyde

21.1 g (95 mmol) of 2,2-diphenylbutyronitrile were dissolved in 100 ml of toluene and, at −78° C. under nitrogen, 95 ml (95 mmol) of a 1 M solution of diisobutylaluminum hydride were added dropwise. The mixture was subsequently stirred at room temperature for 16 hours and then 60 ml of a mixture of saturated ammonium chloride solution and 2 NH₂SO₄ [sic] in the ratio 2:1 was added, and the mixture was stirred for 30 minutes. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO₄ and concentrated under reduced pressure. The crude product was chromatographed on silica gel with dichloromethane. 19.0 g (89%) of 2,2-diphenylbutyraldehyde were obtained as a pale oil.

Example 13 2-Hydroxy-3,3-diphenylvaleronitrile

17.4 g (91.6 mmol) of p-toluenesulfonic acid H₂O, and then 5.9 g (91.6 mmol) of KCN in 25 ml of water, were added at 35° C. to a solution of 19.09 g (84.8 mmol) of 2,2-diphenylbutyraldehyde in 97 ml of THF (abs.). The mixture was then stirred at 40° C. for 4 hours and at room temperature for 16 hours. The mixture was evaporated to 1/3 of the volume, water was added, and the phases were separated. The aqueous phase was then extracted three times with ethyl acetate, and the combined organic phases were washed with 10% strength sodium disulfite solution, dried over MgSO₄ and concentrated under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/acetic acid (20:1). 19.5 g (92%) of 2-hydroxy-3,3-diphenylvaleronitrile were obtained as a pale oil.

¹H-NMR [CDCl₃], δ=0.7 (t, 3H); 2.2-2.5 (m, 3H); 5.25 (d, 1H); 7.1-7.4 (m, 10H).

Example 14 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleronitrile

7.0 g (27.9 mmol) of 2-hydroxy-3,3-diphenylvaleronitrile were dissolved in 100 ml of DMF (abs.) and, under nitrogen, 7.57 g (55.7 mmol) of potassium carbonate and 6.1 g (27.9 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added, and the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, and the residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO₄, and the solvent was evaporated off. The crude product was chromatographed on silica gel with n-heptane/ethyl acetate (20:1). 8.8 g (81%) of product were obtained.

¹H-NMR [CDCl₃], δ=0.8 (t, 3H); 2.45 (dq, 2H); 3.95 (s, 6H), 5.8 (s, 1H); 6.25 (s, 1H); 7.2-7.4 (m, 10H).

Example 15 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleric Acid

0.5 g (1.3 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleronitrile was dissolved in 5 ml of ethanol and, after addition of 5 ml f conc. HCI, the mixture was reflxued for 3 hours. The mixture was then concentrated under reduced pressure, and the residue was taken up in water and extracted twice with ethyl acetate. The combined ethyl acetate phases were dried over MgSO₄ and evaporated. The residue was chromatographed by MPLC on reversed phase material with acetonitrile/water as elnent [sic]. 0.17 g (32%) of 2-(4,6-dimethoxy-2-pyrimidinyloxyl-3,3-diphenylvaleric [sic] acid of melting point 78-87° C. was obtained.

¹H-NMR [DMSO-d₆], δ=0.7 (t, 3H); 2.2-2.55 (m, 2H); 3.85 (s, 6H); 5.9 (s, 2H), 70-74 (m, 10H); 12.7 (s, broad, 1H).

The examples indicated in the following Table 1 can be prepared by the methods described at the outset:

Example 16

Receptor binding data are measured by the binding assay described above for the compounds listed below.

The results are shown in Table 2.

TABLE 2 Receptor binding data (K_(i) values) Compound ET_(A) [nM/1] [sic] ET_(B) [nM/1] [sic] I-3 4 325 I-3 Enantiomer I 0.85 73 I-3 Enantiomer I 450 >720 I-1 25 950 I-2 3.5 290 I-11 20 1400 I-12 4 250 I-15 4 540 I-20 5 445

TABLE 1 I

No. R¹ R⁴ R⁵ R⁶ R² X R³ Y W I-1 OH Phenyl Phenyl Methyl OCH₃ CH OCH₃ N N I-2 OH Phenyl Phenyl Methyl CH₃ CH OCH₃ N N I-3 OH Phenyl Phenyl Methyl CH₃ CH CH₃ N N I-4 OH Phenyl Phenyl Methyl —O—CH₂—CH₂—C OCH₃ N N I-5 OH Phenyl Phenyl Methyl —CH₂—CH₂—CH₂—C OCH₃ N N I-6 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl OCH₃ CH OCH₃ N N I-7 OH Phenyl Phenyl Methyl Ethyl CH Ethyl N N I-8 OH Phenyl Phenyl Methyl Ethyl CH CH₃ N N I-9 OH Phenyl Phenyl Ethyl Ethyl CH OCH₃ N N I-10 OH 4-Me-Phenyl 4-Me-Phenyl Ethyl OCH₃ CH OCH₃ N N I-11 OH Phenyl Phenyl Ethyl OCH₃ CH OCH₃ N N I-12 OH Phenyl Phenyl Ethyl CH₃ CH OCH₃ N N I-13 OCH₃ Phenyl Phenyl Ethyl CH₃ CH OCH₃ N N I-14 OBenzyl Phenyl Phenyl Ethyl CH₃ CH OCH₃ N N I-15 OH Phenyl Phenyl Ethyl CH₃ CH CH₃ N N I-16 OH Phenyl Phenyl Ethyl —O—CH₂—CH₂—C OCH₃ N N I-17 OH Phenyl Phenyl Ethyl —CH₂—CH₂—CH₂—CH₂ OCH₃ N N I-18 OH 4-F-Phenyl 4-F-Phenyl Ethyl CH₃ CH OCH₃ N N I-19 OH 4-F-Phenyl 4-F-Phenyl Ethyl CH₃ CH CH₃ N N I-20 OH Phenyl Phenyl HO—CH₂ CH₃ CH OCH₃ N N I-21 OH Phenyl Phenyl HO—CH₂ CH₃ CH OCH₃ N N I-22 OH Phenyl Phenyl HO—CH₂ CH₃ CH Ethyl N N I-23 OH Phenyl Phenyl HO—CH₂ —O—CH₂—CH₂—C OCH₃ N N I-24 OH Phenyl Phenyl HO—CH₂ —O—CH═CH—C OCH₃ N N I-25 OH Phenyl Phenyl HO—CH₂—CH₂ CH₃ CH CH₃ N N I-26 OH Phenyl Phenyl HO—CH₂—CH₂ OCH₃ CH CH₃ N N I-27 OBenzyl Phenyl Phenyl HO—CH₂—CH₂ OCH₃ CH CH₃ N N I-28 OH Phenyl Phenyl Benzyl-O—CH₂ CH₃ CH CH₃ N N I-29 OH Phenyl Phenyl 4-Me-Benzyl CH₃ CH CH₃ N N O—CH₂ I-30 OH Phenyl Phenyl 4-Me-Benzyl CH₃ CH CH₃ N N O—CH₂ I-31 OH Phenyl Phenyl HO—CH₂—(HO— CH₃ CH OCH₃ N N CH)—CH₂ I-32 OH Phenyl Phenyl HO—CH₂—(HO— CH₃ CH CH₃ N N CH)—CH₂ I-33 OH Phenyl Phenyl HO—CH₂—(HO— —O—CH₂—CH₂C OCH₃ N N CH)—CH₂ I-34 OH Phenyl Phenyl Cl—CH₂—CH₂ CH₃ CH Ethyl N N I-35 OH Phenyl Phenyl Cl—CH₂—CH₂ OCH₃ CH OCH₃ N N I-36 OH Phenyl Phenyl Propyl CH₃ CH CH₃ N N I-37 OH Phenyl Phenyl Propyl OCH₃ CH OCH₃ N N I-38 OH Phenyl Phenyl Propyl CH₃ CH CH₃ N N I-39 OH Phenyl Phenyl Propyl —CH₂—CH₂—CH₂—C OCH₃ N N I-40 OH Phenyl Phenyl Propyl —O—CH₂—CH₂—C OCH₃ N N I-41 OH Phenyl Phenyl iso-Propyl CH₃ CH OCH₃ N N I-42 OH 4-Cl-Phenyl 4-Cl-Phenyl Ethyl CH₃ CH CH₃ N N I-43 OH 4-Cl-Phenyl 4-Cl-Phenyl Ethyl CH₃ CH CH₃ N N I-44 OBenzyl Phenyl Phenyl Ethyl CH₃ CH CH₃ N N I-45 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂ I-46 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂ I-47 OH Phenyl Phenyl 4-Cl-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂ I-48 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-49 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-50 OH Phenyl Phenyl 4-Cl-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-51 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ CH OCH₃ N N CH₂—CH₂—CH₂ I-52 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ CH OCH₃ N N CH₂—CH₂—CH₂ I-53 OH Phenyl Phenyl 4-Cl-Phenyl- CH₃ CH OCH₃ N N CH₂—CH₂—CH₂ I-54 OH Phenyl Phenyl 4-OMe-Phenyl- —O—CH₂—CH₂—C CH₃ N N CH₂—CH₂—CH₂ I-55 OH Phenyl Phenyl 4-Me-Phenyl- —O—CH₂—CH₂—C CH₃ N N CH₂—CH₂—CH₂ I-56 OH Phenyl Phenyl 4-Cl-Phenyl- —O—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂ I-57 OH 4-F-Phenyl 4-F-Phenyl 4-OMe-Phenyl- —O—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂ I-58 OH 4-F-Phenyl 4-F-Phenyl 4-OMe-Phenyl- —O—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂ I-59 OH 4-F-Phenyl 4-F-Phenyl 4-Cl-Phenyl- —O—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂ I-60 OH 4-F-Phenyl 4-F-Phenyl 4-OMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-61 OH 4-F-Phenyl 4-F-Phenyl 4-Me-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-62 OH 4-F-Phenyl 4-F-Phenyl 4-Cl-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-63 OH 4-Me-Phenyl 4-Me-Phenyl 4-OMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-64 OH 4-Me-Phenyl 4-Me-Phenyl 4-Me-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-65 OH 4-Me-Phenyl 4-Me-Phenyl 4-Cl-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-66 OH Phenyl Phenyl HOOC—CH₂ CH₃ CH CH₃ N N I-67 OH Phenyl Phenyl HOOC—CH₂ CH₃ CH CH₃ N N I-68 OH Phenyl Phenyl HOOC—CH₂ —O—CH₂—CH₂—C OCH₃ N N I-69 OH Phenyl Phenyl HOOC—CH₂ —CH₂—CH₂—CH₂—C OCH₃ N N I-70 OH Phenyl Phenyl HOOC—CH₂ Ethyl CH CH₃ N N I-71 OH Phenyl Phenyl HOOC—CH₂ Ethyl CH Ethyl N N I-72 OH Phenyl Phenyl HOOC—CH₂—CH₂ OCH₃ CH CH₃ N N I-73 OH Phenyl Phenyl HOOC—CH₂—CH₂ CH₃ CH CH₃ N N I-74 OH Phenyl Phenyl HOOC—CH₂—CH₂ Ethyl CH CH₃ N N I-75 OH Phenyl Phenyl HOOC—CH₂—CH₂ —O—CH₂—CH₂—C OCH₃ N N I-76 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl OCH₃ CH OCH₃ N N I-77 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl CH₃ CH OCH₃ N N I-78 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl CH₃ CH CH₃ N N I-79 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl CH₃ CH Ethyl N N I-80 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl —O—CH₂—CH₂—C OCH₃ N N I-81 OH 4-OMe-Phenyl 4-OMe-Phenyl Ethyl OCH₃ CH OCH₃ N N I-82 OH 4-OMe-Phenyl 4-OMe-Phenyl Ethyl CH₃ CH OCH₃ N N I-83 OH 4-OMe-Phenyl 4-OMe-Phenyl Ethyl CH₃ CH CH₃ N N I-84 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-Me-Benzyl- CH₃ CH OCH₃ N N O—CH₂ I-85 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-Me-Benzyl- CH₃ CH CH₃ N N O—CH₂ I-86 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-Me-Benzyl- CH₃ CH Ethyl N N O—CH₂ I-87 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Benzyl- OCH₃ CH CH₃ N N O—CH₂ I-88 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Benzyl- CH₃ CH CH₃ N N O—CH₂ I-89 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Benzyl- —O—CH₂—CH₂—C OCH₃ N N O—CH₂ I-90 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-91 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-92 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Phenyl- —O—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂ I-93 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ CH OCH₃ N N CH₂—CH₂—CH₂—CH₂ I-94 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂—CH₂ I-95 OH Phenyl Phenyl 4-OMe-Phenyl- —O—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂—CH₂ I-96 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ CH Ethyl N N CH₂—CH₂—CH₂—CH₂ I-97 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ CH OCH₃ N N CH₂—CH₂—CH₂—CH₂ I-98 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂—CH₂ I-99 OH Phenyl Phenyl 4-Me-Phenyl- —O—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂—CH₂ I-100 OH Phenyl Phenyl 4-Me-Phenyl- Ethyl CH CH₃ N N CH₂—CH₂—CH₂—CH₂ I-101 OH Phenyl Phenyl Methyl CH₃ CH SCH₃ N N I-102 OH Phenyl Phenyl Methyl N(CH₃)₂ CH N(CH₃)₂ N N I-103 OH Phenyl Phenyl Methyl OCH₃ CH SCH₃ N N I-104 OH Phenyl Phenyl Ethyl CH₃ CH SCH₃ N N I-105 OH Phenyl Phenyl Ethyl N(CH₃)₂ CH N(CH₃)₂ N N I-106 OH Phenyl Phenyl iso-Propyl CH₃ CH SCH₃ N N I-107 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ CH SCH₃ N N CH₂—CH₂—CH₂ I-108 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ CH SCH₃ N N CH₂—CH₂—CH₂ I-109 OH Phenyl Phenyl 4-SMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-110 OH Phenyl Phenyl 4-SMe-Phenyl- OCH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-111 OH Phenyl Phenyl 4-SMe-Phenyl- O—CH₂—CH₂—C— OCH₃ N N CH₂—CH₂—CH₂ I-112 OH Phenyl Phenyl 4-SMe-Phenyl- CH₂—CH₂—CH₂—C— OCH₃ N N CH₂—CH₂—CH₂ I-113 OH 4-F-Phenyl 4-F-Phenyl 4-SMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂— I-114 OH 4-F-Phenyl 4-F-Phenyl 4-SMe-Phenyl- CH₃ CH OCH₃ N N CH₂—CH₂—CH₂ I-115 OH 4-Me-Phenyl 4-Me-Phenyl 4-SMe-Phenyl- OCH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-116 OH 4-Me-Phenyl 4-Me-Phenyl 4-SMe-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-117 OH 4-Me-Phenyl 4-Me-Phenyl 4-SMe-Phenyl- O—CH₂—CH₂—C— OCH₃ N N CH₂—CH₂—CH₂ I-118 OH Phenyl Phenyl 4-Ethyl-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-119 OH Phenyl Phenyl HO—CH₂— CH₃ CH SCH₃ N N I-120 OH Phenyl Phenyl HO—CH₂—CH₂ CH₃ CH SCH₃ N N I-121 OH Phenyl Phenyl HOOC—CH₂— CH₃ CH SCH₃ N N CH₂ I-122 OH Phenyl Phenyl Methyl OCH₃ N OCH₃ N N I-123 OH Phenyl Phenyl Methyl CH₃ N OCH₃ N N I-124 OH Phenyl Phenyl Methyl CH₃ N CH₃ N N I-125 OH Phenyl Phenyl Methyl Ethyl N Ethyl N N I-126 OH Phenyl Phenyl Methyl Ethyl N CH₃ N N I-127 OH Phenyl Phenyl Ethyl Ethyl N OCH₃ N N I-128 OH Phenyl Phenyl Ethyl OCH₃ N OCH₃ N N I-129 OH Phenyl Phenyl Ethyl CH₃ N OCH₃ N N I-130 OH Phenyl Phenyl Ethyl CH₃ N CH₃ N N I-131 OH Phenyl Phenyl HO—CH₂ CH₃ N OCH₃ N N I-132 OH Phenyl Phenyl HO—CH₂ CH₃ N CH₃ N N I-133 OH Phenyl Phenyl HO—CH₂ CH₃ N Ethyl N N I-134 OH Phenyl Phenyl HO—CH₂—CH₂ CH₃ N CH₃ N N I-135 OH Phenyl Phenyl Benzyl-O—CH₂ CH₃ N CH₃ N N I-136 OH Phenyl Phenyl 4-Me-Benzyl- CH₃ N CH₃ N N O—CH₂ I-137 OH Phenyl Phenyl 4-OMe-Benzyl- CH₃ N CH₃ N N O—CH₂ I-138 OH Phenyl Phenyl HO—CH₂— CH₃ N OCH₃ N N (HO—CH)— CH₂ I-139 OH Phenyl Phenyl Propyl CH₃ N OCH₃ N N I-140 OH Phenyl Phenyl Propyl CH₃ N CH₃ N N I-141 OH Phenyl Phenyl Propyl OCH₃ N OCH₃ N N I-142 OH Phenyl Phenyl iso-Propyl CH₃ N CH₃ N N I-143 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl OCH₃ N OCH₃ N N I-144 OH 4-OMe-Phenyl 4-OMe-Phenyl Ethyl CH₃ N OCH₃ N N I-145 OH 4-OMe-Phenyl 4-OMe-Phenyl Ethyl CH₃ N CH₃ N N I-146 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl CH₃ N CH₃ N N I-147 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Phenyl- CH₃ N CH₃ N N CH₂— CH₂—CH₂ I-148 OH 4-OMe-Phenyl 4-OMe-Phenyl 4-OMe-Phenyl- CH₃ N OCH₃ N N CH₂— CH₂—CH₂ I-149 OH 4-Me-Phenyl 4-Me-Phenyl Ethyl CH₃ N OCH₃ N N I-150 OH 4-Me-Phenyl 4-Me-Phenyl Methyl CH₃ N CH₃ N N I-151 OH 4-Me-Phenyl 4-Me-Phenyl 4-OMe-Phenyl- CH₃ N CH₃ N N CH₂— CH₂—CH₂ I-152 OH 4-Me-Phenyl 4-Me-Phenyl 4-Me-Phenyl- CH₃ N CH₃ N N CH₂— CH₂—CH₂ I-153 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ N CH₃ N N CH₂— CH₂—CH₂ I-154 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ N CH₃ N N CH₂— CH₂—CH₂ I-155 OH Phenyl Phenyl 4-SMe-Phenyl- CH₃ N CH₃ N N CH₂—CH₂—CH₂ I-156 OH Phenyl Phenyl 4-SMe-Phenyl- OCH₃ N CH₃ N N CH₂—CH₂—CH₂ I-157 OH Phenyl Phenyl HOOC—CH₂ CH₃ N CH₃ N N I-158 OH Phenyl Phenyl Methyl CH₃ N SCH₃ N N I-159 OH Phenyl Phenyl Methyl N(CH₃)₂ N N(CH₃)₂ N N I-160 OH Phenyl Phenyl Ethyl CH₃ N SCH₃ N N I-161 OH Phenyl Phenyl Methyl OCH₃ N OCH₃ CH N I-162 OH Phenyl Phenyl Methyl OCH₃ N CH₃ CH N I-163 OH Phenyl Phenyl Methyl CH₃ N OCH₃ CH N I-164 OH Phenyl Phenyl Methyl CH₃ N CH₃ CH N I-165 OH Phenyl Phenyl Methyl CH₃ N Ethyl CH N I-166 OH Phenyl Phenyl Methyl Ethyl N Ethyl CH N I-167 OH Phenyl Phenyl Methyl Ethyl N CH₃ CH N I-168 OH Phenyl Phenyl Methyl OCH₃ N SCH₃ CH N I-169 OH Phenyl Phenyl Methyl OCH₃ N CF₃ CH N I-170 OH Phenyl Phenyl Ethyl OCH₃ N OCH₃ CH N I-171 OH Phenyl Phenyl Ethyl CH₃ N CH₃ CH N I-172 OH Phenyl Phenyl Ethyl OCH₃ N CH₃ CH N I-173 OH Phenyl Phenyl Ethyl CH₃ N OCH₃ CH N I-174 OH Phenyl Phenyl Ethyl CH₃ N Ethyl CH N I-175 OH Phenyl Phenyl Ethyl Ethyl N Ethyl CH N I-176 OH Phenyl Phenyl Ethyl Ethyl N CH₃ CH N I-177 OH Phenyl Phenyl Ethyl OCH₃ N SCH₃ CH N I-178 OH Phenyl Phenyl Ethyl OCH₃ N CF₃ CH N I-179 OH Phenyl Phenyl Propyl CH₃ N CH₃ CH N I-180 OH Phenyl Phenyl Propyl OCH₃ N CH₃ CH N I-181 OH Phenyl Phenyl Propyl CH₃ N OCH₃ CH N I-182 OH Phenyl Phenyl HO—CH₂ CH₃ N CH₃ CH N I-183 OH Phenyl Phenyl HO—CH₂ OCH₃ N CH₃ CH N I-184 OH Phenyl Phenyl HO—CH₂ CH₃ N OCH₃ CH N I-185 OH Phenyl Phenyl HO—CH₂(OH— CH₃ N CH₃ CH N CH)—CH₂ I-186 OH Phenyl Phenyl HO—CH₂(OH— CH₃ N OCH₃ CH N CH)—CH₂ I-187 OH Phenyl Phenyl HO—CH₂(OH— OCH₃ N CH₃ CH N CH)—CH₂ I-188 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-189 OH Phenyl Phenyl 4-OMe-Phenyl- OCH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-190 OH Phenyl Phenyl 4-OMe-Phenyl- CH₃ N OCH₃ CH N CH₂—CH₂—CH₂ I-191 OH Phenyl Phenyl 4-OMe-Phenyl- Ethyl N CH₃ CH N CH₂—CH₂—CH₂ I-192 OH Phenyl Phenyl 4-SMe-Phenyl- OCH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-193 OH Phenyl Phenyl 4-SMe-Phenyl- CH₃ N OCH₃ CH N CH₂—CH₂—CH₂ I-194 OH Phenyl Phenyl 4-SMe-Phenyl- OCH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-195 OH Phenyl Phenyl 4-SMe-Phenyl- Ethyl N Ethyl CH N CH₂—CH₂—CH₂ I-196 OH Phenyl Phenyl 4-SMe-Phenyl- CH₃ N Ethyl CH N CH₂—CH₂—CH₂ I-197 OH Phenyl Phenyl HOOC—CH₂ CH₃ N CH₃ CH N I-198 OH Phenyl Phenyl HOOC—CH₂ CH₃ N Ethyl CH N I-199 OH Phenyl Phenyl HOOC—CH₂ CH₃ N OCH₃ CH N I-200 OH Phenyl Phenyl HOOC—CH₂ OCH₃ N CH₃ CH N I-201 OH 4-F-Phenyl 4-F-Phenyl Methyl CH₃ N CH₃ CH N I-202 OH 4-OMe-Phenyl 4-OMe-Phenyl Methyl CH₃ N CH₃ CH N I-203 OH 4-Me-Phenyl 4-MePhenyl Methyl CH₃ N CH₃ CH N I-204 OH 4-Me-Phenyl 4-MePhenyl Ethyl CH₃ N CH₃ CH N I-205 OH 4-Me-Phenyl 4-Me-Phenyl Ethyl CH₃ N OCH₃ CH N I-206 OH 4-Me-Phenyl 4-Me-Phenyl Ethyl OCH₃ N CH₃ CH N I-207 OH 4-Me-Phenyl 4-Me-Phenyl Ethyl Ethyl N CF₃ CH N I-208 OH 4-Me-Phenyl 4-Me-Phenyl HOOC—CH₂—CH₂ CH₃ N CH₃ CH N I-209 OH 4-Me-Phenyl 4-Me-Phenyl HOOC—CH₂—CH₂ OCH₃ N CH₃ CH N I-210 OH 4-Me-Phenyl 4-Me-Phenyl HOOC—CH₂—CH₂ Ethyl N CH₃ CH N I-211 OH Phenyl Phenyl HOOC—CH₂—CH₂ CH₃ N CH₃ CH N I-212 OH Phenyl Phenyl HOOC—CH₂—CH₂ OCH₃ N CH₃ CH N I-213 OH Phenyl Phenyl HOOC—CH₂—CH₂ Ethyl N CH₃ CH N I-214 OH Phenyl Phenyl HOOC—CH₂—CH₂ Ethyl N CF₃ CH N I-215 OH Phenyl Phenyl HOOC—CH₂—CH₂ CH₃ N OCH₃ CH N I-216 OH Phenyl Phenyl HOOC—CH₂—CH₂ CH₃ N Ethyl CH N I-217 OH Phenyl Phenyl HOOC—CH₂—CH₂ CF₃ N Ethyl CH N I-218 OH Phenyl Phenyl HO—CH₂—(HO— CF₃ N Ethyl CH N CH)—CH₂ I-219 OH Phenyl Phenyl HO—CH₂—(HO— CH₃ N Ethyl CH N CH)—CH₂ I-220 OH Phenyl Phenyl HO—CH₂—(HO— Ethyl N CH₃ CH N CH)—CH₂ I-221 OH Phenyl Phenyl (HO—CH₂)₂CH—CH₂ CH₃ N CH₃ CH N I-222 OH Phenyl Phenyl (HO—CH₂)₂CH—CH₂ OCH₃ N CH₃ CH N I-223 OH Phenyl Phenyl (HO—CH₂)₂CH—CH₂ CH₃ N OCH₃ CH N I-224 OH Phenyl Phenyl (HO—CH₂)₂CH—CH₂ CH₃ N Ethyl CH N I-225 OH Phenyl Phenyl Methyl CH=CH—CH=CH—C CH₃ CH N I-226 OH Phenyl Phenyl Methyl CH=CH—CH═CH—C H CH N I-227 OH Phenyl Phenyl Methyl CH₃ CH CH₃ CH N I-228 OH Phenyl Phenyl Methyl CH₃ CH OCH₃ CH N I-229 OH Phenyl Phenyl Methyl CH₃ CH Ethyl CH N I-230 OH Phenyl Phenyl Methyl Ethyl CH CH₃ CH N I-231 OH Phenyl Phenyl Ethyl CH═CH—CH═CH—C CH₃ CH N I-232 OH Phenyl Phenyl Ethyl CH═CH—CH═CH—C H CH N I-233 OH Phenyl Phenyl Propyl CH═CH—CH═CH—C CH₃ CH N I-234 OH Phenyl Phenyl Ethyl CH₂—CH₂—CH₂—C CH₃ CH N I-235 OH Phenyl Phenyl Methyl CH₂—CH₂—CH₂—C CH₃ CH N I-236 OH Phenyl Phenyl Propyl CH₂—CH₂—CH₂—C CH₃ CH N I-237 OH Phenyl Phenyl Ethyl CH₃ CH Ethyl CH N I-238 OH Phenyl Phenyl Ethyl CH₃ CH CH₃ CH N I-239 OH Phenyl Phenyl Ethyl Ethyl CH CH₃ CH N I-240 OH Phenyl Phenyl Ethyl CH₃ CH OCH₃ CH N I-241 OH Phenyl Phenyl Methyl OCH₃ XH CH₃ CH N I-242 OH Phenyl Phenyl Methyl O—CH₂—CH₂—C H CH N I-243 OH Phenyl Phenyl Methyl O—CH₂—CH₂—C CH₃ CH N I-244 OH Phenyl Phenyl Ethyl OCH₃ CH CH₃ CH N I-245 OH Phenyl Phenyl Ethyl O—CH₂—CH₂—C H CH N I-246 OH Phenyl Phenyl Ethyl O—CH₂—CH₂—C CH₃ CH N I-247 OH Phenyl Phenyl Ethyl O—CH₂—O—C H CH N I-248 OH Phenyl Phenyl Ethyl O—CH₂—O—C CH₃ CH N I-249 OH Phenyl Phenyl Ethyl CH₃ CH CH═CH—CH═CH—C N I-250 OH Phenyl Phenyl Ethyl OCH₃ CH CH═CH—CH═CH—C N I-251 OH Phenyl Phenyl Methyl CH₃ CH CH═CH—CH═CH—C N I-252 OH Phenyl Phenyl Methyl OCH₃ CH CH═CH—CH═CH—C N I-253 OH Phenyl Phenyl Methyl CH₃ CH O—CH₂—O—C N I-254 OH Phenyl Phenyl Methyl OCH₃ CH O—CH₂—O—C N I-255 OH Phenyl Phenyl Ethyl CH₃ CH O—CH₂—O—C N I-256 OH Phenyl Phenyl Ethyl OCH₃ CH O—CH₂—O—C N I-257 OH Phenyl Phenyl Ethyl CH₃ CH CH₂—CH₂—O—C N I-258 OH Phenyl Phenyl Ethyl OCH₃ CH CH₂—CH₂—O—C N I-259 OH Phenyl Phenyl Methyl CH₃ CH CH₂—CH₂—O—C N I-260 OH Phenyl Phenyl Methyl OCH₃ CH CH₂—CH₂—O—C N I-261 OH Phenyl Phenyl Methyl CH₃ CH N═CH—NH—C N I-262 OH Phenyl Phenyl Methyl OCH₃ CH N═CH—NH—C N I-263 OH Phenyl Phenyl Ethyl CH₃ CH N═CH—NH—C N I-264 OH Phenyl Phenyl Ethyl OCH₃ CH N═CH—NH—C N I-265 OH Phenyl Phenyl Ethyl CH₃ CH CH═CH—NH—C N I-266 OH Phenyl Phenyl Ethyl OCH₃ CH CH═CH—NH—C N I-267 OH Phenyl Phenyl HO—CH₂ CH₃ CH CH═CH—NH—C N I-268 OH Phenyl Phenyl HO—CH₂ OCH₃ CH CH═CH—NH—C N I-269 OH Phenyl Phenyl HO—CH₂—CH₂ CH₃ CH CH═CH—NH—C N I-270 OH Phenyl Phenyl HO—CH₂—CH₂ OCH₃ CH CH═CH—NH—C N I-271 OH Phenyl Phenyl Methyl CH₃ CH CH═CH—NH—C N I-272 OH Phenyl Phenyl Methyl OCH₃ CH CH═CH—NH—C N I-273 OH Phenyl Phenyl Methyl CH₃ N CH═CH—NH—C N I-274 OH Phenyl Phenyl Methyl OCH₃ N CH═CH—NH—C N I-275 OH Phenyl Phenyl Ethyl CH₃ N CH═CH—NH—C N I-276 OH Phenyl Phenyl Ethyl OCH₃ N CH═CH—NH—C N I-277 OH Phenyl Phenyl HO—CH₂ CH₃ N CH═CH—NH—C N I-278 OH Phenyl Phenyl HO—CH₂ OCH₃ N CH═CH—NH—C N I-279 OH Phenyl Phenyl Methyl CH₃ N N═CH—NH—C N I-280 OH Phenyl Phenyl Ethyl CH₃ N N═CH—NH—C N I-281 OH Phenyl Phenyl Propyl CH₃ N N═CH—NH—C N I-282 OH Phenyl Phenyl HO—CH₂—CH₂ CH₃ N N═CH—NH—C N I-283 OH Phenyl Phenyl Phenyl-CH₂—CH₂ CH₃ N N═CH—NH—C N I-284 OH Phenyl Phenyl Phenyl- CH₃ N N═CH—NH—C N CH₂—CH₂—CH₂ I-285 OH Phenyl Phenyl 4-Me-Phenyl- CH₃ N N═CH—NH—C N CH₂—CH₂ I-286 OH Phenyl Phenyl Methyl CH₃ N O—CH₂—CH₂—C N I-287 OH Phenyl Phenyl Ethyl CH₃ N O—CH₂—CH₂—C N I-288 OH Phenyl Phenyl HO—CH₂ CH₃ N O—CH₂—CH₂—C N I-289 OH Phenyl Phenyl HO—CH₂—CH₂ CH₃ N O—CH₂—CH₂—C N I-290 OH Phenyl Phenyl Phenyl-CH₂—CH₂ CH₃ N O—CH₂—CH₂—C N I-291 OH Phenyl Phenyl Phenyl-CH₂—CH₂ CH₃ N CH₂—CH₂—O—C N I-292 OH Phenyl Phenyl Methyl CH₃ N CH₂—CH₂—O—C N I-293 OH Phenyl Phenyl Ethyl CH₃ N CH₂—CH₂—O—C N I-294 OH Phenyl Phenyl Ethyl CH₃ N CH₂—CH₂—CH₂—C N I-295 OH Phenyl Phenyl Ethyl OCH₃ N CH₂—CH₂—CH₂—C N I-296 OH Phenyl Phenyl Methyl CH₃ N CH₂—CH₂—CH₂—C N I-297 OH Phenyl Phenyl Methyl OCH₃ N CH₂—CH₂—CH₂—C N I-298 OH Phenyl Phenyl HO—CH₂ CH₃ N CH₂—CH₂—CH₂—C N I-299 OH Phenyl Phenyl HO—CH₂—CH₂ CH₃ N CH₂—CH₂—CH₂—C N I-300 OH Phenyl Phenyl Phenyl-CH₂—CH₂ CH₃ N CH₂—CH₂—CH₂—C N I-301 OH Phenyl Phenyl 4-MeO-Phenyl- CH₃ N CH₂—CH₂—CH₂—C N CH₂—CH₂—CH₂ I-302 OH 2-Naphthyl Phenyl Methyl OCH₃ N OCH₃ CH N I-303 OH 2-Naphthyl Phenyl Methyl CH₃ N CH₃ CH N I-304 OH 2-Naphthyl Phenyl Methyl OCH₃ N CH₃ CH N I-305 OH 2-Naphthyl Phenyl Methyl CH₃ N OCH₃ CH N I-306 OH 2-Naphthyl Phenyl Methyl Ethyl N CH₃ CH N I-307 OH 2-Naphthyl Phenyl Ethyl OCH₃ N OCH₃ CH N I-308 OH 2-Naphthyl Phenyl Ethyl CH₃ N CH₃ CH N I-309 OH 2-Naphthyl Phenyl Ethyl OCH₃ N CH₃ CH N I-310 OH 2-Naphthyl Phenyl Ethyl CH₃ N OCH₃ CH N I-311 OH 2-Naphthyl Phenyl Ethyl Ethyl N CH₃ CH N I-312 OH 2-Naphthyl Phenyl Propyl CH₃ N CH₃ CH N I-313 OH 2-Naphthyl Phenyl Propyl OCH₃ N CH₃ CH N I-314 OH 2-Naphtyl [sic] Phenyl HO—CH₂ CH₃ N CH₃ CH N I-315 OH 2-Naphtyl [sic] Phenyl HO—CH₂ OCH₃ N CH₃ CH N I-316 OH 2-Naphtyl [sic] Phenyl HO—CH₂ OCH₃ N OCH₃ CH N I-317 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ OCH₃ N OCH₃ CH N I-318 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ CH₃ N CH₃ CH N I-319 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ OCH₃ N CH₃ CH N I-320 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- CH₃ N CH₃ CH N CH₂—CH₂ I-321 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- OCH₃ N CH₃ CH N CH₂—CH₂ I-322 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ N OCH₃ CH N CH₂—CH₂ I-323 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ N CH₃ CH N CH₂—CH₂ I-324 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- CH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-325 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- OCH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-326 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-327 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ N CH₃ CH N CH₂—CH₂—CH₂ I-328 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ N OCH₃ CH N CH₂—CH₂—CH₂ I-329 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-330 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-331 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH OCH₃ N N CH₂—CH₂—CH₂ I-332 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₂—CH₂—CH₂—C CH₃ N N CH₂—CH₂—CH₂ I-333 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₂—CH₂—CH₂—C H N N CH₂—CH₂—CH₂ I-334 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₂—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂ I-335 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- CH₂—CH₂—CH₂—C CH₃ N N CH₂—CH₂—CH₂ I-336 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- CH₂—CH₂—CH₂—C H N N CH₂—CH₂—CH₂ I-337 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- CH₂—CH₂—CH₂—C OCH₃ N N CH₂—CH₂—CH₂ I-338 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ CH₂—CH₂—CH₂—C CH₃ N N I-339 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ CH₂—CH₂—CH₂—C H N N I-340 OH 2-Naphtyl [sic] Phenyl HO₂C—CH₂ CH₂—CH₂—CH₂—C CH₃ N N I-341 OH 2-Naphtyl [sic] Phenyl HO₂C—CH₂ CH₂—CH₂—CH₂—C H N N I-342 OH 2-Naphtyl [sic] Phenyl Methyl CH₂—CH₂—CH₂—C CH₃ N N I-343 OH 2-Naphtyl [sic] Phenyl Methyl CH₂—CH₂—CH₂—C H N N I-344 OH 2-Naphtyl [sic] Phenyl Ethyl CH₂—CH₂—CH₂—C CH₃ N N I-345 OH 2-Naphtyl [sic] Phenyl Ethyl CH₂—CH₂—CH₂—C H N N I-346 OH 2-Naphtyl [sic] Phenyl Ethyl CH₃ CH CH₃ N N I-347 OH 2-Naphtyl [sic] Phenyl Ethyl OCH₃ CH CH₃ N N I-348 OH 2-Naphtyl [sic] Phenyl Ethyl Ethyl CH CH₃ N N I-349 OH 2-Naphtyl [sic] Phenyl Ethyl OCH₃ CH OCH₃ N N I-350 OH 2-Naphtyl [sic] Phenyl Methyl CH₃ CH CH₃ N N I-351 OH 2-Naphtyl [sic] Phenyl Methyl OCH₃ CH CH₃ N N I-352 OH 2-Naphtyl [sic] Phenyl Methyl OCH₃ CH OCH₃ N N I-353 OH 2-Naphtyl [sic] Phenyl HO—CH₂ CH₃ CH CH₃ N N I-354 OH 2-Naphtyl [sic] Phenyl HO—CH₂ OCH₃ CH CH₃ N N I-355 OH 2-Naphtyl [sic] Phenyl HO—CH₂ OCH₃ CH OCH₃ N N I-356 OH 2-Naphtyl [sic] Phenyl HO—CH₂ Ethyl CH CH₃ N N I-357 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ CH₃ CH CH₃ N N I-358 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ OCH₃ CH CH₃ N N I-359 OH 2-Naphtyl [sic] Phenyl HO—CH₂—CH₂ OCH₃ CH OCH₃ N N I-360 OH 2-Naphtyl [sic] Phenyl HO₂C—CH₂ CH₃ CH CH₃ N N I-361 OH 2-Naphtyl [sic] Phenyl HO₂C—CH₂ OCH₃ CH CH₃ N N I-362 OH 2-Naphtyl [sic] Phenyl HO₂C—CH₂ OCH₃ CH CH₃ N N I-363 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂ I-364 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- OCH₃ CH CH₃ N N CH₂—CH₂ I-365 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- OCH₃ CH OCH₃ N N CH₂—CH₂ I-366 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-367 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- OCH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-368 OH 2-Naphtyl [sic] Phenyl p-Me-Phenyl- OCH₃ CH OCH₃ N N CH₂—CH₂—CH₂ I-369 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-370 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-371 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ CH CH₃ N N CH═CH₂—CH₂ I-372 OH 2-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH CH₃ N N CH═CH₂—CH₂ I-373 OH 1-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ CH CH₃ N N CH═CH₂—CH₂ I-374 OH 1-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH CH₃ N N CH═CH₂—CH₂ I-375 OH 1-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH OCH₃ N N CH═CH₂—CH₂ I-376 OH 1-Naphtyl [sic] Phenyl p-MeO-Phenyl- CH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-377 OH 1-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH CH₃ N N CH₂—CH₂—CH₂ I-378 OH 1-Naphtyl [sic] Phenyl p-MeO-Phenyl- OCH₃ CH OCH₃ N N CH₂—CH₂—CH₂ I-379 OH 1-Naphtyl [sic] Phenyl Phenylmethyl- CH₃ CH CH₃ N N O—CH₂ I-380 OH 1-Naphtyl [sic] Phenyl Phenylmethyl- OCH₃ CH CH₃ N N O—CH₂ I-381 OH 1-Naphtyl [sic] Phenyl HO—CH₂ CH₃ CH CH₃ N N I-382 OH 1-Naphtyl [sic] Phenyl HO—CH₂ OCH₃ CH CH₃ N N I-383 OH 1-Naphtyl [sic] Phenyl HO—CH₂—CH₂ CH₃ CH CH₃ N N I-384 OH 1-Naphtyl [sic] Phenyl HO—CH₂—CH₂ OCH₃ CH CH₃ N N I-385 OH 1-Naphtyl [sic] Phenyl Propyl CH₃ CH CH₃ N N I-386 OH 1-Naphtyl [sic] Phenyl Propyl OCH₃ CH CH₃ N N I-387 OH 1-Naphtyl [sic] Phenyl Ethyl OCH₃ CH OCH₃ N N I-388 OH 1-Naphtyl [sic] Phenyl Ethyl OCH₃ CH CH₃ N N I-389 OH 1-Naphtyl [sic] Phenyl Ethyl CH₃ CH CH₃ N N I-390 OH 1-Naphtyl [sic] Phenyl Methyl CH₃ CH CH₃ N N I-391 OH 1-Naphtyl [sic] Phenyl Methyl OCH₃ CH CH₃ N N I-392 OH 1-Naphtyl [sic] Phenyl Methyl OCH₃ CH OCH₃ N N I-393 OH 3,4-Dioxomethyl- Phenyl Methyl CH₃ CH CH₃ N N enylphenyl [sic] I-394 OH 3,4-Dioxomethyl- Phenyl Methyl OCH₃ CH CH₃ N N enylphenyl [sic] I-395 OH 3,4-Dioxomethyl- Phenyl Methyl OCH₃ CH OCH₃ N N enylphenyl [sic] I-396 OH 3,4-Dioxomethyl- Phenyl Ethyl CH₃ CH CH₃ N N enylphenyl [sic] I-397 OH 3,4-Dioxomethyl- Phenyl Ethyl OCH₃ CH CH₃ N N enylphenyl [sic] I-398 OH 3,4-Dioxomethyl- Phenyl Ethyl OCH₃ CH OCH₃ N N enylphenyl [sic] I-399 OH 3,4-Dioxomethyl- Phenyl HO—CH₂ CH₃ CH CH₃ N N enylphenyl [sic] I-400 OH 3,4-Dioxomethyl- Phenyl HO—CH₂ OCH₃ CH CH₃ N N enylphenyl [sic] I-401 OH 3,4-Dioxomethyl- Phenyl HO—CH₂—CH₂ CH₃ CH CH₃ N N enylphenyl [sic] I-402 OH 3,4-Dioxomethyl- Phenyl HO—CH₂—CH₂ OCH₃ CH CH₃ N N enylphenyl [sic] I-403 OH 3,4-Dioxomethyl- Phenyl p-Me-Phenyl- CH₃ CH CH₃ N N enylphenyl [sic] CH₂—CH₂—CH₂ I-404 OH 3,4-Dioxomethyl- Phenyl p-Me-Phenyl- OCH₃ CH CH₃ N N enylphenyl [sic] CH₂—CH₂—CH₂ I-405 OH 3,4-Dioxomethyl- Phenyl p-MeO-Phenyl- CH₃ CH CH₃ N N enylphenyl [sic] CH₂—CH₂—CH₂ I-406 OH 3,4-Dioxomethyl- Phenyl p-MeO-Phenyl- OCH₃ CH CH₃ N N enylphenyl [sic] CH₂—CH₂—CH₂ I-407 OH 3,4-Dioxomethyl- Phenyl p-MeO-Phenyl- OCH₃ CH OCH₃ N N enylphenyl [sic] CH₂—CH₂—CH₂ 

We claim:
 1. An α-hydroxy carboxylic acid compound of the formula I

where R is a group

where R¹ has the following meanings: b) a succinylimidoxy group c) a 5-membered heteroaromatic ring selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which ring is bonded to CH via a ring nitrogen atom and which may carry one or two halogen atoms or one or two C₁-C₄-alkyl or one or two C₁-C₄-alkoxy groups; d) a group

where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R⁹ is C₁-C₄-alkyl, C₃-C₇-cycloalkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or unsubstituted or substituted phenyl which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, mercapto, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino; e) a radical OR¹⁰, where R¹⁰ is: hydrogen, the cation of an alkali metal lithium, sodium, potassium or the cation of an alkaline earth metal calcium, magnesium and barium, and physiologically tolerated alkylammonium ion or the ammonium ion; C₃-C₈-cycloalkyl, C₁-C₈-alkyl, CH₂ phenyl which can be substituted on the phenyl radical by one or more of the following radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, a C₃-C₆-alkenyl or C₃-C₆-alkynyl group, it being possible for this group in turn to carry one to five halogen atoms; a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxymercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino; a 5-membered heteroaromatic system which is linked via a nitrogen atom and has one to three nitrogen atoms, and which may carry one or two halogen atoms and/or one or two of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio; f) a radical

where R¹¹ is: C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, it being possible for these radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio, and/or a phenyl radical; phenyl which is unsubstituted or substituted by one or more members selected from the group consisting of halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, and C₁-C₄-dialkylamino; h)

where R¹³ and R¹⁴ can be identical or different and have the following meanings: hydrogen, C₁-C₇-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-alkenyl, C₃-C₇-alkynyl, benzyl, phenyl, wherein the phenyl radicals are optionally unsubstituted or substituted by one or more members selected from the group consisting of halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, hydroxyl, C₁-C₄-alkoxy, mercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, and C₁-C₄-dialkylamino, or R¹³ and R¹⁴ together form a C₄-C₇-alkylene chain which is closed to a ring, is unsubstituted or substituted by C₁-C₄-alkyl and may contain a hetero atom selected from the group consisting of oxygen, sulfur or nitrogen, or R is tetrazolyl or cyano; W is nitrogen, C—NO₂, a CH group when one or more of the substituents R², R³, R¹⁵ and/or R¹⁶ are a nitro group, or when X and/or Y are nitrogen; R² and R³ are phenyl, optionally substituted once to three times by halogen, hydroxyl, amino, mono- or dialkyl (C₁-C₃)-amino, C₁-C₃-alkyl, C₁-C₃-alkoxy, mercapto or C₁-C₃-alkylthio, carboxyl or C₁-C₃-alkylcarboxyl; X is nitrogen or CR¹⁵ where R¹⁵ is hydrogen or C₁-C₅-alkyl, optionally substituted once or twice by hydroxyl or carboxyl; C₁-C₆-alkoxy, C₁-C₆-alkylthio, phenyl, benzyl, hydroxyl, mercapto, nitro, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, cyano or carboxyl; it is furthermore possible for CR¹⁵ to be linked to R² to give a 5- or 6-membered ring as described above, or CR¹⁵ can form with R³ and its adjacent carbon atom a 5- or 6-membered alkylene or alkylidene ring in each of nitrogen, oxygen or sulfur, and the 5- or 6-membered ring may optionally be substituted once to three times by the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-alkylthio, amino, C₁-C₃-alkylamino, C₁-C₃-dialkylamino or carboxyl; nitrogen in the 5-membered ring may also be substituted by a formyl or acetyl group; Y is nitrogen or CR¹⁶ where R¹⁶ is hydrogen, C₁-C₅-alkyl, C₁-C₅-alkoxy, C₁-C₅-alkylthio, nitro, phenyl, hydroxyl, halogen, cyano, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, mercapto or carboxyl, or R¹⁶ forms together with R³ and its adjacent carbon atom a 5- or 6-membered ring as described above wherein two of X, Y and W are nitrogen and the other is carbon; R⁴ is phenyl, naphthyl, dihydro- or tetrahydronaphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy, phenyl, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino or C₁-C₄-dialkylamino, it being possible for two radicals on adjacent carbon atoms to form, together with the latter, a five- or six-membered ring which is linked by an alkylene or alkylidene group and in which one or more methylene or methylidene groups can be replaced by oxygen; R⁵ can have the same meanings as R⁴, it being possible for R⁴ and R⁵ to be identical or different; and R⁶ is hydrogen, C₁-C₈-alkyl, C₃-C₈-alkenyl or C₃-C₈-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, nitro, cyano, C₁-C₄-alkoxy, hydroxyl, C₁-C₄-alkylthio, mercapto, C₁-C₄-haloalkoxy, carboxyl, C₁-C₄-alkylcarboxy, C₁-C₄-alkylcarbonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, a five- or six-membered heteroaromatic system which has one to three nitrogen atoms and/or one sulfur or oxygen atom and which can carry one to four halogen atoms and/or one or two of the following radicals; C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio; phenyl, naphthyl, which can in turn be substituted one or more times by: halogen, nitro, cyano, hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-haloalkoxy, mercapto, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, C₁-C₄-dialkyl amino or phenoxy; or one of the following radicals:


2. An α-hydroxy carboxylic acid derivative as claimed in claim 1, wherein R is COOH.
 3. An α-hydroxy carboxylic acid compound as claimed in claim 1, wherein at least one of the radicals R⁴ and R⁵ is phenyl.
 4. An α-hydroxy carboxylic acid compound as claimed in claim 3, wherein R⁴ and R⁵ are both phenyl.
 5. An α-hydroxy carboxylic acid compound as claimed in claim 1, wherein R⁶ is C₁-C₈-alkyl, unsubstituted or substituted by OH or C₁-C₄-alkoxy.
 6. An α-hydroxy carboxylic acid compound as claimed in claim 1, wherein X is CH.
 7. A method of treating hypertension, pulmonary hypertension, acute and chronic kidney failure, chronic heart failure, cerebral ischemia, restenosis after angioplasty and prostate cancer, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of an α-hydroxy carboxylic acid compound of the formula I, as defined in claim
 1. 8. A method for inducing endothelin receptor-antagonizing activity which comprises administering a therapeutically effective amount of a compound as defined in claim 1 to a host in need of endothelin receptor-antagonizing activity. 